The role of molecular analyses in the diagnosis and treatment of non-small-cell lung carcinomas

https://doi.org/10.1053/j.semdp.2013.11.007Get rights and content

Abstract

Non-small-cell lung cancer (NSCLC) subtyping has recently been a key factor in determining patient management with novel drugs. In addition, the identification of distinct oncogenic driver mutations frequently associated with NSCLC histotype and coupled to the clinical responses to targeted therapies have revolutionized the impact of histologic type and molecular biomarkers in lung cancer. Several molecular alterations involving different genes (EGFR, KRAS, ALK, BRAF, and HER2) seem to have a remarkable predilection for adenocarcinoma and specific inhibitors of EGFR and ALK are now available for patients with adenocarcinoma harboring the relevant gene alterations. The efficacy of histology-based and molecular-targeted therapies had a deep impact in (1) re-defining classification of lung cancer (particularly adenocarcinomas) and (2) routine clinical practice of pathologists involved in optimization of handling of tissue samples in order to guarantee NSCLC subtyping with the help of immunohistochemistry and adequately preserve tumor cells for molecular analysis. In agreement with the modern multidisciplinary approach to lung cancer, we reviewed here the diagnostic and predictive value of molecular biomarkers according to the clinical, pathologic, and molecular biologist viewpoints.

Introduction

In 2011, lung cancer was the leading cause of cancer-related deaths worldwide.1 Unfortunately, median survival of patients with metastatic disease remains disappointing, with only a small fraction of patients surviving more than 2 years. Non-small-cell lung cancer (NSCLC) represents 85% of all lung cancer diagnoses and is a heterogeneous disease with several biological events driving tumor growth and progression. Enormous efforts in clinical trials over the last 10 years and harmonious cooperation between clinicians and basic scientists have led to the development of new molecularly driven therapies with unprecedented results in some subsets of patients.

The aim of this review is to discuss the role of molecular analysis in the diagnosis and treatment of advanced NSCLC to guide a personalized approach, with a particular focus on the new challenges faced by pathologists dealing with lung cancer.

Section snippets

Personalized treatment for NSCLC: The point of view of the medical oncologist

The last few years have been terribly exciting for clinicians treating patients with advanced NSCLC. After decades of slow progresses and “one-size-fits-all” approach, the era of personalized treatment has eventually arrived. For years, NSCLC patients have been treated with the same chemotherapy, without any clinical or biological selection, and inevitably disappointing results. Recently, we have learned that patient selection is extremely important to select the most appropriate treatment and

Pathologists and molecular analyses in the diagnosis of NSCLC

NSCLC has been considered for several years as one disease, while this definition included various histotype with different “druggable” oncogenic drivers, opening to personalized therapies and a multidisciplinary approach involving physicians, molecular biologists, pharmaceutical companies, as well as pathologists.32, 33, 34, 35, 36 Molecular analyses in NSCLC have been mainly focused on patient prognosis and in prediction of response to novel targeted therapies. Pathologists play a key role in

Pathologists, molecular analyses, and handling of tumor samples

More than 70% of non-small-cell lung cancer (NSCLC) patients present with unresectable advanced disease.127 In such advanced NSCLC patients, the diagnosis is generally achieved through minimally invasive procedures that usually retrieve small biopsies (trans-thoracic fine-needle biopsies and bronchial and trans-bronchial biopsies) or exclusively cytological samples (i.e., fine-needle aspiration and pleural or pericardial effusion), often just adequate to reach a diagnosis of malignancy.

Personalized treatment for NSCLC: The point of view of the molecular biologist

Recent progress in molecular diagnostics of NSCLC has identified epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusion proteins as key genetic alterations that are linked to response to EGFR-TKIs and ALK inhibitors, respectively.3, 4, 5, 136 EGFR has been demonstrated to be able to activate at least two major signaling pathways, including KRAS, which in turn activates BRAF and the MAPK cascade, and phosphatidylinositol 3-kinase (PI3K), which activates

Take-home messages

(1) Pathologists should be conscious that they play a key role in the management of patients with lung cancer in the era of new histology-based therapeutic agents (i.e., pemetrexed and bevacizumab) and targeted molecular therapies (i.e., EGFR inhibitors gefitinib and erlotinib and ALK inhibitor crizotinib).

(2) Pathologists are called to perform more precise subtyping of NSCLC, becoming familiar with immunohistochemistry (antibodies expression and its interpretation), and carefully select the

Acknowledgments

Given the editorial limits, we would apologize to all the authors of interesting original and review works not cited here.

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